Faculty Collaboration Database

Proteasome-dependent down-regulation of activated Stat5A in the nucleus. Blood 2006 Jul 15;108(2):566-74

Date

03/30/2006

Pubmed ID

16569768

Pubmed Central ID

PMC1895487

DOI

10.1182/blood-2005-12-4777

Scopus ID

2-s2.0-33745937881   21 Citations

Abstract

A broad spectrum of cytokines can activate the signal transducer and activator of transcription 5 (Stat5) by inducing a single tyrosine phosphorylation of the molecule. Although the process of Stat5 activation has been well studied, the mechanism by which it is inactivated is not fully understood. We demonstrate that the proteasome inhibitor MG132, but not the nuclear export inhibitor leptomycin B (LMB), stabilizes active nuclear Stat5A, whereas MG132 only partially stabilizes active cytoplasmic Stat5A. Importantly, ubiquitinated Stat5A is detected in the nucleus and the polyubiquitination of active Stat5A is K48 linked, a linkage type targeting proteins for degradation. Ubiquitination of Stat5A is recapitulated in a cell-free system, and Ubc5 is identified as the E2-conjugating enzyme for Stat5A ubiquitination. Interestingly, phosphorylation of Stat5A per se is not required for ubiquitination. Finally, C-terminal deletion analysis of Stat5A localizes the amphipathic region of amino acids 751-762 as a ubiquitination signal, possibly representing an E3 recognition motif. Taken together, these results demonstrate that the down-regulation of nuclear and cytoplasmic active Stat5A is differentially regulated. In the nucleus, ubiquitin/proteasome-mediated protein degradation is the dominant mechanism for the down-regulation of active Stat5A, whereas in the cytoplasm, protein tyrosine phasphatase is a major player in the down-regulation of active Stat5A.

Author List

Chen Y, Dai X, Haas AL, Wen R, Wang D

Author

Demin Wang PhD Assistant Professor in the Microbiology and Immunology department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Animals
Binding Sites
Cell Line
Cell Nucleus
Down-Regulation
Humans
Mice
Phosphorylation
Proteasome Endopeptidase Complex
STAT5 Transcription Factor
Transfection
Tumor Suppressor Proteins
Ubiquitin